As diseases associated with the activity of vanilloid receptor, pain, acute pain, chronic pain, neuropathic pain, post-operative pain, migraine, arthralgia, neuropathies, nerve injury, diabetic neuropathy, neurodegeneration, neurotic skin disorder, stroke, urinary bladder hypersensitiveness, irritable bowel syndrome, a respiratory disorder such as asthma or chronic obstructive pulmonary disease, irritation of skin, eye or mucous membrane, fervescence, stomach-duodenal ulcer, inflammatory bowel disease and inflammatory diseases can be enumerated. The present invention provides pharmaceutical compositions for prevention or treatment of these diseases. Yet, the diseases described above are only for enumeration, not to limit the scope of clinical application of vanilloid receptor agonist.
Capsaicin(8-methyl-N-vanillyl-6-nonenamides; CAP) is a main pungent component in hot pepper. Hot pepper has been used, for a long time, not only as a spice but also as a traditional medicine in the treatment of gastric disorders and when applied locally, for the relief of pain and inflammation (Szallasi and Blumberg, Pharm. Rev., 51, pp159-211, 1999. CAP has a wide spectrum of biological actions, and not only exhibits effects on the cardiovascular and respiratory systems but also induces pain and irritancy on local application. CAP, however, after such induction of pain, induces desensitization, both to CAP itself and also to other noxious stimuli to make the pain stopped. Based on this property, CAP and its analogues such as olvanil, nuvanil, DA-5018, SDZ-249482, resiniferatoxin are either used as analgesic agent, therapeutic agent for incontinentia urinae or skin disorder, or under development (Wriggleworth and Walpore, Drugs of the Future, 23, pp531-538, 1998).
Transmissions of mechanical, thermal and chemical noxious stimuli are mainly occurred by primary afferent nerve fibers of fine unmyelinated nerve(C-fiber) and thin myelinated nerve(A-fiber), and main reaction site of CAP and its analogues called vanilloid is present at the nerve fiber transmitting the noxious stimuli. CAP acts at the receptor existing on these neurons to induce potent stimuli by causing potent inflow of mono-acid and di-valent cations such as calcium and sodium, then exhibits potent analgesic effect by blocking the nervous function (Wood et al.; J. Neurosci., 8, pp3208-3220, 1988). Vanilloid receptor-1(VR) has been recently cloned and its existences becomes clear (Caterina et al.; Nature, 389, pp816-824, 1997). It was clarified that this receptor transmits not only stimuli by CAP analogues(vanilloid) but also various noxious stimuli such as proton and thermal stimuli (Tominaga et al.; Neuron, 21, pp513-543, 1998). Based on this, it is considered that VR functions as a integrative modulator against various noxious stimuli and carries out critical role in transmissions of pain and noxious stimuli. Recently, knock-out mouse in which gene encoding for vanilloid receptor was deleted was prepared (Caterinal et al.; Science, 288, pp306-313, 2000: Davis et al.; Nature, 405, pp183-187, 2000). Compared to normal mice, the mouse was found out to exhibit much reduced reaction to thermal stimuli and thermal pain, while exhibiting no difference in general behavior, reconfirming the importance of the receptor in transmission of noxious signal. However, except proton, no other endogenous ligand, not exogenous ligand such as CAP, actually involved in transmission of noxious stimuli at VR was known.
VR (or CAP receptor) is a specific neuronal membrane recognition site for CAP and related irritant compounds. It is expressed almost exclusively by primary sensory neurons involved in nociception and neurogenic inflammation. The receptor functions as a cation-selective ion channel with a preference for calcium, and its functional subtype, VR-1, activated by both CAP and noxious heat has recently been cloned. Its desensitization caused by specific ligands has been recognized as a promising therapeutic approach to mitigate neuropathic pain and other pathological conditions in which neuropeptides released from primary sensory neurons play a crucial role.
Most exogenous VR agonists which are being developed or used as analgesics are structually related to CAP (i.e., Zostrix™, Olvanil™, SDZ-249482™, and DA-5018™) and resiniferatoxin. Their structures include a common vanilloid ring which appears to be important for agonist activity. However, in a recent report, it was demonstrated that compounds lacking the vanilloid moiety, such as sesquiterpenoid unsaturated dialdehydes or triprenyl phenol, may also activate the receptor. Although receptor antagonists are fewer, several compounds such a capsazepine, which acts competitively at the CAP binding site, the channel blocker ruthenium red and capsazocaine have been reported.
Resiniferatoxin (RTX), a tricyclic diterpene isolated from Euphorbia resinifera, has been regarded as an ultrapotent CAP analogue. Indeed, the specific binding of RTX to the CAP binding site in dorsal root ganglia has been demonstrated with labeled [3H]RTX. RTX is being developed as an ultrapotent sensory neuron desensitizing agent for the treatment of urinary urge incontinence and the pain assoaciated with diabetic neuropathy. Recently, a totally enantiocontrolled synthesis and a conformational analysis of RTX have been reported. However, the pharmacophoric groups of RTX have not yet been clearly defined, although structure-activity studies suggest that the C20-homovanillic moiety, the C3-keto group, and the ortho-ester phenyl group on ring C are crucial structural elements responsible for the extremely high potency of RTX. The lower potency of CAP relative to RTX, on the other hand, may be rationalized by the lack of some of these critical pharmacophoric groups, especially C3-keto group.
U.S. Pat. No. 4,939,149 discloses a method for desensitizing a subject animal by administering a therapeutically effective desensitizing amount of RTX for desensitizing the animal to neurogenic inflammation, to chemically and thermally induced pain and to responses involving sensory afferent pathways sensitive to CAP.
Although a number of vanilloid agonist based on the structures of CAP and RTX have been reported as potential analgesics (e.g., U.S. Pat. No. 5,021,450 discloses homovanillyl diterpene derivatives such as 12-deoxyphorbol 13-phenylacetate 20-homovanillate and mezerein 20-homovanillate as mimics of RTX), these CAP-like analogues are limited by their intrinsic lower potency and narrow therapeutic index. RTX, on the other hand, is of limited availability from natural sources and is difficult to obtain synthetically due to its structural complexity.
The present inventors have made extensive researches to discover novel analgesic agents based on the VR, which has simpler structure than RTX or known RTX- or CAP-like analogues. As results thereof, KP348819 which we invented, disclosed that the new compounds having modifications on C20-homovanillic moiety, the C3-carbonyl, and the ortho-ester phenyl moiety as essential groups for recognition and binding showed potent VR agonist activity in terms of the receptor binding assay and the CAP-activated single channels assay (Lee et al.; Bioorganic & Medicinal Chemistr. Letters, pp2909-2914, 1999). And KPA2000-0048385 which we invented, disclosed that new compounds having modifications on 4-methane sulphone amido instead of 4-hydroxy-3-methoxy phenyl moiety as essential groups for recognition and binding based on the VR showed different receptor agonist activity.
The present invention is to provide novel compounds having modifications on thiocarbamate moiety, the 3-acyloxy2-benzylpropyl, the 4-t-butylbenzyl, and the 4-hydroxy-3-methoxy moiety as essential groups for recognition and binding showed potent VR receptor agonist activity in terms of the receptor binding assay and exhibit analgesic and anti-inflammatory effects while causing no irritancy, and pharmaceutical compositions containing the same.